Journal ArticleDOI
Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial
Alice T. Shaw,Tae Min Kim,Lucio Crinò,Cesare Gridelli,Katsuyuki Kiura,Geoffrey Liu,Silvia Novello,Alessandra Bearz,Oliver Gautschi,Tony Mok,Makoto Nishio,Giorgio V. Scagliotti,David R. Spigel,S. Deudon,Cheng Zheng,Serafino Pantano,Patrick Urban,Cristian Massacesi,Kalyanee Viraswami-Appanna,Enriqueta Felip +19 more
Reads0
Chats0
TLDR
Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy and was compared with single-agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy.Abstract:
Summary Background Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK -rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK -rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK -rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0–2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking [block size of four]; stratified by WHO performance status [0 vs 1–2] and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m 2 or docetaxel 75 mg/m 2 [investigator choice], every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01828112, and is ongoing but no longer recruiting patients. Findings Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 [34%] to pemetrexed, 73 [63%] to docetaxel, and three [3%] discontinued before receiving treatment). Median follow-up was 16·5 months (IQR 11·5–21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1–6·9] for ceritinib vs 1·6 months [1·4–2·8] for chemotherapy; hazard ratio 0·49 [0·36–0·67]; p vs 12 [11%] in the chemotherapy group). The most frequent grade 3–4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 [21%] of 115 vs two [2%] of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 [21%] vs one [1%]), and increased aspartate aminotransferase concentration (16 [14%] vs one [1%] in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one [7%] cerebrovascular accident and one [7%] respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression. Interpretation These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population. Funding Novartis Pharmaceuticals Corporation.read more
Citations
More filters
Journal ArticleDOI
Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up †
Silvia Novello,Fabrice Barlesi,Raffaele Califano,Raffaele Califano,Tanja Cufer,Simon Ekman,M. Giaj Levra,Keith M. Kerr,Sanjay Popat,Martin Reck,Suresh Senan,G Simo,Johan Vansteenkiste,Sanne Peters +13 more
TL;DR: The ESMO Guidelines Committee concluded that current state-of-the-art oncology practices in France, Belgium, and the Netherlands are suitable for frontline use and recommend further research into these practices.
Journal ArticleDOI
Systemic Therapy for Locally Advanced and Metastatic Non-Small Cell Lung Cancer: A Review.
TL;DR: Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease and improvements in overall survival.
Journal ArticleDOI
Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study
Benjamin Solomon,Benjamin Besse,Benjamin Besse,Todd M. Bauer,Enriqueta Felip,Ross A. Soo,D. Ross Camidge,Rita Chiari,Alessandra Bearz,Chia-Chi Lin,Shirish M. Gadgeel,Gregory J. Riely,Eng Huat Tan,Takashi Seto,Leonard P. James,Jill S. Clancy,Antonello Abbattista,Jean-Francois Martini,Joseph Chen,Gerson Peltz,Holger Thurm,Sai-Hong Ignatius Ou,Alice T. Shaw +22 more
TL;DR: Overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer and safety data for all treated patients (EXP1-6) are presented.
Journal ArticleDOI
A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)
Joaquin Mateo,Debyani Chakravarty,R. Dienstmann,S. Jezdic,Abel Gonzalez-Perez,Nuria Lopez-Bigas,Charlotte K.Y. Ng,Philippe L. Bedard,Giampaolo Tortora,J.-Y. Douillard,E.M. Van Allen,Nikolaus Schultz,Charles Swanton,Fabrice Andre,Lajos Pusztai +14 more
TL;DR: The first version of the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) defines clinical evidence-based criteria to prioritise genomic alterations as markers to select patients for targeted therapies.
Journal ArticleDOI
Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update
Nasser H. Hanna,Bryan J. Schneider,Sarah Temin,Sherman Baker,Julie R. Brahmer,Peter M. Ellis,Laurie E. Gaspar,Laurie E. Gaspar,Rami Y. Haddad,Paul J. Hesketh,Dharamvir Jain,Ishmael Jaiyesimi,David H. Johnson,Natasha B. Leighl,Tanyanika Phillips,Gregory J. Riely,Andrew G. Robinson,Rafael Rosell,Joan H. Schiller,Navneet Singh,David R. Spigel,Janis O. Stabler,Joan Tashbar,Gregory A. Masters +23 more
TL;DR: This guideline update reflects changes in evidence since the previous guideline update and is conditional on the basis of histology, PD-L1 status, and/or the presence of contraindications.
References
More filters
Journal ArticleDOI
Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer.
TL;DR: Recent progress in the development of new ALK inhibitors and in the molecular diagnosis of ALK rearrangement-positive NSCLC is summarized.
Journal ArticleDOI
Ceritinib (LDK378): A Potent Alternative to Crizotinib for ALK-Rearranged Non–Small-Cell Lung Cancer
TL;DR: The current knowledge on acquired resistance of crizotinib known as a first-in-class ALK inhibitor and potential solutions to improve the cost-effectiveness and future directions of ceritinib to be a potent alternative to crizotib for ALK-rearranged non-small-cell lung cancer are presented.
Journal ArticleDOI
1225ooverall and intracranial (ic) efficacy results and time to symptom deterioration in profile 1014: 1st-line crizotinib vs pemetrexed − platinum chemotherapy (ppc) in patients (pts) with advanced alk-positive non-squamous non-small cell lung cancer (nsclc)
Ben Solomon,Enriqueta Felip,Fiona H Blackhall,Tony Mok,Dong Wook Kim,Y-L. Wu,Kazuhiko Nakagawa,Tarek Mekhail,Jolanda Paolini,Tiziana Usari,Shrividya Iyer,Arlene Reisman,Keith D. Wilner,Jennifer M. Tursi,Frederico Cappuzzo +14 more
TL;DR: Crizotinib treatment showed significant improvements in PFS and TTDS vs PPC, a numerical improvement in IC TTP, and an acceptable safety profile, establishing crizotinIB as the standard of care for pts with treatment-naive advanced ALK-positive non-squamous NSCLC.
Journal ArticleDOI
P3.02a-036 Phase 1 Study of Ceritinib 450 mg or 600 mg Taken with a Low-Fat Meal versus 750 mg in Fasted State in ALK+ Metastatic NSCLC: Topic: Miscellaneous
Rafal Dziadziuszko,Dong Wan Kim,Alessandra Bearz,Scott A. Laurie,Mark J. McKeage,Keunchil Park,Sang-We Kim,Vanessa Q. Passos,Karen Osborne,Yvonne Y. Lau,Jessie Gu,Byoung Chul Cho +11 more
Journal Article
Combining Inhibitors of ALK and ROS1 With Other Agents for the Treatment of Non-Small Cell Lung Cancer
TL;DR: These are distinct subsets of lung cancer patients, and the authors rarely if ever see overlap of ALK and ROS1 rearrangement.
Related Papers (5)
Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer
First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study
Jean-Charles Soria,Daniel Shao-Weng Tan,Rita Chiari,Yi-Long Wu,Luis Paz-Ares,Juergen Wolf,Sarayut Lucien Geater,Sergey Orlov,Diego Cortinovis,Chong-Jen Yu,Maximillian Hochmair,Alexis B. Cortot,Chun-Ming Tsai,Denis Moro-Sibilot,Rosario Garcia Campelo,Tracey McCulloch,Paramita Sen,Margaret Dugan,Serafino Pantano,Fabrice Branle,Cristian Massacesi,Gilberto de Castro +21 more
Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer
Alice T. Shaw,Dong Wan Kim,Kazuhiko Nakagawa,Takashi Seto,Lucio Crinò,Myung-Ju Ahn,Tommaso De Pas,Benjamin Besse,Benjamin Solomon,Fiona H Blackhall,Yi-Long Wu,Michael Thomas,Kenneth J. O'Byrne,Denis Moro-Sibilot,D. Ross Camidge,Tony Mok,Vera Hirsh,Gregory J. Riely,Shrividya Iyer,V. Tassell,Anna Polli,Keith D. Wilner,Pasi A. Jänne +22 more